Dementia afflicts a large and rapidly growing number of individuals and their families. A majority of cases are caused by Alzheimer's Disease (AD), but substantial percentages are attributed to other causes. Frontotemporal dementia (FTD) is the third most common cause of neurodegenerative dementia, after AD and Diffuse Lewy Body Disease. The clinical features of FTD include memory deficits, behavioral abnormalities, personality changes and language impairments. Amongst FTD cases, the most common cause has been recognized recently to be inherited mutation in the Progranulin (PGRN) gene. This genetic insight has the potential to lead to rational and effective therapies for FTD. The success of such translation to clinical benefit requires understanding how PGRN acts in the brain and how its mutation results in disease. The current proposal seeks to define PGRN action using molecular and genetic tools. The long- term goal is the identification of targets for FTD treatment and prevention. In Preliminary Studies, we examined PGRN binding to the cell surface and have identified a high affinity neuronal binding site. The 50% PGRN decrease causative in FTD cases is mimicked in mice lacking one copy of the PGRN gene, and is full corrected by genetic ablation of the binding partner. These findings indicate that the PGRN binding protein has a crucial in determining PGRN levels and hence FTD. In the proposed Specific Aims, the relevance for this binding partner for FTD pathology and neurological dysfunction will be assessed in preclinical studies. This work may provide new avenues for therapeutic intervention for FTDs which currently have not treatment. PUBLIC HEALTH RELEVANCE: FrontoTemporal Dementia is one of the most common forms of degenerative dementia after Alzheimer's Disease, but there are no treatments. Molecular studies have revealed that a 50% reduction in PGRN protein can cause this neurodegeneration. In this project, we test the hypothesis that a neuronal binding protein for PGRN participates in its action. If validated, this hypothesis predicts that this PGRN binding partner will be a novel target for therapeutic development for FrontoTemporal Dementia.